Effectiveness of eribulin as first-line or second-line chemotherapy for HER2-negative hormone-resistant advanced or metastatic breast cancer: findings from the multi-institutional, prospective, observational KBCRN A001: E-SPEC study.

BACKGROUND: The optimal positioning of eribulin treatment remains unclear. This study aimed to investigate the effectiveness of eribulin administration as first- and second-line chemotherapy in patients with endocrine-resistant advanced or metastatic breast cancer (AMBC) in the real-world clinical setting. METHODS: This multi-institutional prospective cohort study enrolled patients with triple-negative AMBC or estrogen receptor-positive AMBC refractory to at least one previous endocrine therapy. The overall survival (OS) from the start of first-line (OS1) and second-line chemotherapy (OS2) was assessed. Data analysis included real-world chemotherapy sequences of first- to third-line chemotherapy regimens. The adjusted hazard ratio (HR) with 95% confidence interval (CI) for treatment regimen comparison was calculated using a stratified proportional hazards model. RESULTS: Among 201 patients enrolled, 180 were included in the final analysis. Eribulin was administered as first- and second-line chemotherapy to 46 (26.6%) and 70 (47.9%) patients, respectively. Median OS1 and OS2 were 2.25 (95% CI 1.07-2.68) and 1.75 (95% CI, 1.28-2.45) years for first- and second-line eribulin, respectively. Oral 5-FU followed by eribulin had a numerically longer OS1 (2.84 years) than the other sequences. Among patients who proceeded to second-line or later chemotherapy, the median OS1 for those treated with anthracycline or taxane as first- or second-line (n = 98) was 2.56 years (95% CI 2.27-2.74), while it was 2.87 years (95% CI 2.20-4.32) for those who avoided anthracycline and taxane as first- and second-line (n = 48) (adjusted HR, 1.20; 95% CI 0.70-2.06). In the exploratory analysis, OS1 was 2.55 (95% CI 2.14-2.75) and 2.91 years (95% CI 2.61-4.32) for those aged < 65 and ≥ 65 years, respectively (adjusted HR of ≥ 65, 0.91; 95% CI 0.56-1.46). CONCLUSIONS: Eribulin or oral 5-FU administration in first- and second-line chemotherapy without anthracycline/taxane was acceptable in the real-world setting. TRIAL REGISTRATION: This study is registered with Clinical Trials.gov (NCT 02,551,263).

A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using multicatheter interstitial brachytherapy: clinical results with a median follow-up of 60 months.

BACKGROUND: We carried out the first multi-institutional prospective study on accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy in a shorter period for early breast cancer in Japan. METHODS: Patient eligibility criteria included positive hormone receptors, tumors ≤ 3 cm and TNM stage pN0M0. After breast-conserving surgery (Japanese cylindrical resection) and histological confirmation of negative surgical margins and the absence of lymph node metastasis, applicator implantation was performed either postoperatively or intraoperatively. High-dose-rate brachytherapy of 36 Gy in 6 fractions was delivered. RESULTS: Forty-six patients from six institutions received this treatment regimen, and the median follow-up time was 60 months (range 57-67 months). The median resected breast tissue volume was 81 cm3 (range 28-260 cm3). No Grade 4 late sequela, local recurrence nor death due to breast cancer were observed. Grade 2-3 sequelae such as rib fracture (2%), soft tissue necrosis (9%), fibrosis (20%), and breast pain (9%) were observed. The resected breast tissue volumes of the patients who had Grade ≥ 2 fibrosis and Grade < 2 fibrosis were 105.9 ± 32.3 cm3 and 76.3 ± 45.6 cm3, respectively, p = 0.02. The overall cosmetic outcome score of Excellent/Good was 74% at 60 months after APBI. Grade ≥ 1 fibrosis was observed in 44% and 92% of patients who scored Excellent/Good and Fair/Poor, respectively, p = 0.004. CONCLUSIONS: This study showed excellent local control and survival results with minimal late sequelae.

Extension toward the Trapezius in a Transversely Oriented Latissimus Dorsi Flap for Breast Reconstruction.

A transverse paddle latissimus dorsi (LD) flap has the advantage that if the skin paddle is placed in the transverse bra line, the donor site scar is well hidden by underwear. With this transfer, medial back tissues are usually moved to the medial area of the reconstructed breast following 180 degree rotation. Because these tissues are thinner than the lateral thoracic area, the medial part of the reconstructed breast sometimes becomes flatter than expected. METHODS: To add bulk in the medial lower quadrant for giving an impression of an outward-expanding breast, we modified the LD flap by adding a part of the trapezius muscle. Seven patients underwent mastectomy and simultaneously received a modified LD flap. To hide the donor site scar beneath underwear, the skin paddle needed to be oriented transversely. The additional harvested tissues were tested for vascularity by fluorescence following intravascular injections of indocyanine green. If this was negative, the tissue was not used for breast reconstruction. Postoperatively, another surgeon judged whether this modification had contributed favorably to the reconstructed medial lower quadrant. RESULTS: Indocyanine green testing was positive in six cases. The shape of the lower medial quadrant was judged as good in five of the seven cases. Complications included an animation deformity of the LD muscle, donor site seroma, and donor site wound dehiscence. CONCLUSION: This transversely oriented LD flap with extension to the trapezius muscle placed at the bra-line is one option to add bulk to the medial lower quadrant of the reconstructed breast when an additional scar is not desired for cosmetic reasons.

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants.

The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.

Two Cases of the Vascular Territory of a Single-pedicled Deep Inferior Epigastric Perforator Flap with a Vertical Midline Abdominal Scar.

: The deep inferior epigastric perforator (DIEP) flap is becoming the gold standard for breast reconstruction using autologous tissue. If there are scars in the abdomen from previous surgery, it is necessary to judge the indication for using this flap carefully. Particularly in cases with vertical midline scars, the blood flow supply to the zone II can be compromised. Even when patients have a median abdominal scar, it has been reported that the blood flow can extend beyond the scar and reach several centimeters to about half of zone II. We performed breast reconstruction using DIEP flaps for 2 patients with vertical midline scars in the lower abdomen. Indocyanine green angiography was conducted intraoperatively to confirm the vascular territory with a single pedicle before cutting off the flap. One patient showed fluorescence contrast on the contralateral side across the midline scar. However, the fluorescence contrast was absent across the midline scar in the other patient. Based on this result, we investigated the possible vascular territory of a single pedicled DIEP flap in patients with vertical midline abdominal scars. We suggest that successful blood supply to zone II of a single-pedicled DIEP flap in a patient with a vertical midline abdominal scar is related to the location of the perforator and the property of the tissue in the midline near the perforator. However, because it is difficult to predict the vascular territory of a single pedicle before surgery, intraoperative evaluation using such techniques such as indocyanine green fluorescence imaging is important.

Case report of a dose-volume histogram analysis of rib fracture after accelerated partial breast irradiation: interim analysis of a Japanese prospective multi-institutional feasibility study.

We initiated the first multi-institutional prospective study of accelerated partial breast irradiation for early breast cancer in Japan. Our early clinical results showed that the treatment methods were technically reproducible between institutions and showed excellent disease control at a median follow-up of 26 months in our previous report. At present, total 46 patients from six institutions underwent the treatment regimen from October 2009 to December 2011, and the median follow-up time was 60 months (range, 57-67 months). In 46 patients, we experienced one patient who had rib fracture as a late complication. The dose-volume histogram (DVH) result of this patient was analyzed. The D0.01cc, D0.1cc, and D1cc values of the patient were 913, 817, and 664 cGy per fraction, respectively. These values were the highest values in 46 patients. The average D0.01cc, D0.1cc, and D1cc values of the other 45 patients were 546, 500, and 419, respectively, cGy per fraction. From this result, DVH values showing high-dose irradiated volume (D0.01cc, D0.1cc, and D1cc) seem to be a good predictive factor of rib fracture for accelerated partial breast irradiation. However, further investigation is necessary because of the small number of patients investigated.

Uncertainty of cosmetic evaluation after accelerated partial breast irradiation: interim analysis of a Japanese prospective multi-institutional feasibility study.

PURPOSE: We conducted a multi-institutional prospective study on accelerated partial breast irradiation (APBI) using interstitial brachytherapy. The clinical results over a minimum follow-up period of 30 months are presented here. MATERIALS AND METHODS: Forty-six patients with breast cancer were treated with breast-conserving surgery and postoperative APBI. After confirmation of negative surgical margins and negative lymph nodes, a high-dose-rate brachytherapy protocol of 36 Gy/6 fractions was carried out. All clinical data were prospectively collected using the Common Terminology Criteria for Adverse Events ver. 3.0. RESULTS: No recurrence was observed. Cumulative rates of grade 2 or higher late sequelae were 25% for fibrosis, 2% for fractures, 9% for pain, and 9% for soft tissue necrosis. Rates of excellent or good cosmetic results as assessed by the physician and patient were 93 and 89% at the 12-month follow-up and 76 and 74% at the 30-month follow-up, respectively. Large volumes of resected tissue in small breasts were associated with fibrosis of grade 2 or higher. CONCLUSION: APBI in Japanese women provides satisfactory clinical results except for cosmetic outcomes. There is some difficulty with the assessment of fibrosis and cosmetic outcomes, especially in patients with small breasts. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000001677.

[Efficacy and Safety of Neoadjuvant Chemotherapy Containing Nanoparticle Albumin-Bound Paclitaxel (NabPTX) in Operable Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer].

The efficacy and safety of nanoparticle albumin-bound paclitaxel (nabPTX)-containing neoadjuvant chemotherapy (NAC) were investigated in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Thirteen HER2-positive patients received NAC containing nabPTX or paclitaxel between June 2008 and December 2014. Of 13 HER2-positive patients, those who received nabPTX-containing NAC showed an 85.7% (6/7) pathological complete response (pCR) rate, whereas those who received paclitaxel-containing NAC showed a pCR rate of 50.0% (3/6). While 5 of 7 patients who received nabPTX-containing NAC developed Grade 3/4 neutropenia, none of them developed febrile neutropenia. Grade 1/2 peripheral neuropathy developed in all 7 patients who received nabPTX-containing NAC. This therapy may be a safe and effective treatment for HER2-positive breast cancer patients.

A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: clinical results with a median follow-up of 26 months.

BACKGROUND: A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy was performed. The first clinical results were reported with a median follow-up of 26 months. PATIENTS AND METHODS: Forty-six female breast cancer patients with positive hormone receptors and tumors ≤3 cm, pN0M0, completed the protocol treatment. After breast-conserving surgery and histological confirmation of negative surgical margins and pN0, brachytherapy applicators were implanted either postoperatively (n = 45) or intraoperatively (n = 1). High-dose-rate brachytherapy of 36 Gy/6 fractions was delivered. All clinical data were prospectively collected using case report forms and the Common Terminology Criteria for Adverse Events ver.3.0. RESULTS: At the median follow-up of 26 months, no breast cancer recurrence of any type was observed. Sequelae ≥G2 were dermatitis (G2, 7 %), fibrosis (G2, 11 %; G3, 4 %), fracture (G2, 2 %), pain (G2, 7 %; G3, 2 %), and soft tissue necrosis (G2, 6 %). Cosmetic outcomes evaluated by excellent/good scores were 100 % at pre-therapy (n = 46), 94 % at 12 months (n = 46), and 81 % at 24 months (n = 36), respectively. CONCLUSIONS: Disease control and sequelae were satisfactory due to the strict eligibility and protocol-defined treatment parameters. The cosmetic outcomes were comparable to those of previous Japanese breast-conserving therapy series.

A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: treatment planning and quality assurance.

BACKGROUND: In Japan, breast-conserving surgery with closed cavity has generally been performed for breast cancer patients, and accelerated partial breast irradiation (APBI) is considered difficult because Asian females generally have smaller breast sizes than Western females. Therefore, common identification of target and treatment plan method in APBI is required. A prospective multicenter study was conducted in Japan to determine institutional compliance with APBI using high-dose-rate interstitial brachytherapy (ISBT) designed for Japanese female patients. METHODS: For this study, 46 patients were recruited at eight institutions from January 2009 to December 2011. The reproducibility of the ISBT-APBI plan was evaluated using three criteria: (1) minimum clinical target volume dose with a clip dose ≥ 6 Gy/fraction, (2) irradiated volume constraint of 40-150 cm(3), and (3) uniformity of dose distribution, expressed as the dose non-uniformity ratio (DNR, V150/V100) < 0.35. The ISBT-APBI plan for each patient was considered reproducible when all three criteria were met. When the number of non-reproducible patients was ≤ 4 at study completion, APBI at this institution was considered statistically reproducible. RESULTS: Half of the patients (52 %) had a small bra size (A/B cup). The mean values of the dose-constrained parameters were as follows: Vref, 117 cm(3) (range, 40-282), DNR, 0.30 (range, 0.22-0.51), and clip dose, 784 cGy (range, 469-3146). A total of 43/46 treatment plans were judged to be compliant and ISBT-APBI was concluded to be reproducible. CONCLUSIONS: This study showed that multi-institutional ISBT-APBI treatment plan was reproducible for small breast patient with closed cavity.

Prevalence and risk factors of bone metastasis and skeletal related events in patients with primary breast cancer in Japan.

BACKGROUND: Bone metastasis (BM) is important for studying systemic spread of breast cancer. It often causes skeletal-related events (SREs) that worsen quality of life. We investigated the prevalence and risk factors for BM and SRE using a dataset from the Breast Oncology Research Network (BORN) in Japan. PATIENTS AND METHODS: We collected data on primary breast cancer patients with node-positive or node-negative disease at intermediate to high risk of recurrence. The risk factors affecting the BM-free rate, SRE-free rate and overall survival were analyzed by using the Cox proportional hazard model. RESULTS: Data of 1,779 patients who were diagnosed with breast cancer during 2003-2005 were collected from the BORN and 1,708 cases were used for analysis. The median follow-up duration was 5.71 years. BM developed in 193 cases (11.3 %) and the BM-free rate at 5 years was 89.2 %. The annual hazard ratio of BM development differs remarkably according to the tumor subtype. SREs occurred in 133 (68.9 %) out of 193 patients and the SRE-free rate at 5 years was 92.6 %. In the multivariate analysis, clinical stage (P < 0.0001), number of lymph node (LN) metastases (P = 0.0029), tumor subtype (P = 0.034) and progesterone receptor status (P = 0.038) were independently significant risk factors for BM-free rate, but only clinical stage (P < 0.0001) and number of LN metastases (P = 0.0004) significantly correlated with SRE-free rate. CONCLUSIONS: This retrospective study clarifies the prevalence and risk factors for BM and SRE in Japanese breast cancer patients. Our results show the importance of considering subtype in the care of BM and SRE.

Uterine changes during tamoxifen, toremifene, and other therapy for breast cancer: evaluation with magnetic resonance imaging.

PURPOSE: We have performed pelvic magnetic resonance imaging (MRI) in patients undergoing breast cancer surgery before and after adjuvant drug therapy. Our purpose was to detect any radiographic uterine changes induced by various types of adjuvant therapy on pre- and postmenopausal patients by evaluating prospectively performed MRI. MATERIALS AND METHODS: Between September 2004 and December 2007, a total of 41 women with breast cancer (11 premenopausal, 30 postmenopausal) were enrolled. All underwent MRI of the pelvis before and after drug therapy, and uterine changes were evaluated. Postoperative drugs used were selective estrogen receptor modulators (SERMs) including tamoxifen and toremifene (n = 18), aromatase inhibitors (n = 13), and anticancer drugs (n = 10). RESULTS: Only the postmenopausal patients receiving SERMs showed a significant increase in endometrial thickness: from 2.4 +/- 0.4 mm before therapy to 4.5 +/- 2.6 mm after therapy (P = 0.0485). No statistically significant endometrial change was evident in postmenopausal patients treated with aromatase inhibitors (P = 0.573) or anticancer drugs (P = 0.754). Also, in premenopausal patients treated with SERMs or anticancer drugs, the change in endometrial thickness was not statistically significant (P = 0.958, 0.370). CONCLUSION: This prospective study using MRI has demonstrated that uterine changes associated with adjuvant drugs for breast cancer occur exclusively in postmenopausal patients receiving SERMs.

[Stratification with respect to hormone receptor and HER 2/neu in the treatment of metastatic breast cancer; sensitivity to taxane].

Of 231 patients with recurrent or metastatic breast cancer treated in Hiei Hospital between January 2001 and March 2005, for whom data on hormone receptor (HR) and HER 2/neu were available, we retrospectively analyzed the association of the response rate with HR and HER 2 in 172 patients treated with taxane in whom the treatment response could be evaluated. Among the patients treated with taxane alone,the response rates were 37.5% (n=67) in the HR (+) patients and 14.6% (n=41) in the HR (-) patients (p=0.0131). In particular, taxane resistance was suggested in the HR (-)/HER 2 (-) patients (response rate: 4.2%, n=24). Concerning combination therapy with trastuzumab and taxane, the response rate were 52.8% in the HR (+)/HER 2 (+) patients and 60.4% in the HR (-)/HER 2 (+) patients. In 27 of these patients, single therapy with taxane was switched to combination therapy with taxane and trastuzumab after they became resistant to taxane, and 8.3% of the HR (+)/HER 2 (+) patients and 53.3% of the HR (-)/HER 2 (+) patients responded to this combination therapy (p=0.0192), suggesting the synergistic effects of the two agents in HR (-)/HER 2 (+) patients. Therefore, HR and HER 2 were associated with the sensitivity to a chemotherapeutic agent, taxane. Stratification with respect to HR and HER 2 is important in the treatment of metastatic breast cancer. In particular, therapeutic strategies for HR (-)/HER 2 (-) patients with a poor prognosis must be established in the future.